Stroke is a leading cause of disability and death, yet relatively few biochemical and genetic risk factors for ischemic stroke have been identified. The aim of this application is to examine novel risk factors for ischemic stroke in women. The risk of ischemic stroke has been closely associated with obesity, insulin resistance, and diabetes. Exogenous estrogens clearly increase the risk of ischemic stroke and recent evidence suggests a reduced risk of stroke with estrogen lowering therapy. Adipocytes are responsible for peripheral conversion of steroid hormones and express cytokines and hormones (adipokines) that may influence inflammation and cardiovascular risk. Increased cellular turnover and other factors may lead to reduction in telomere length and reduced capacity for healing. We will examine sex hormones and adipokines as novel pathways related to adiposity and risk of ischemic stroke. Specifically, we will test whether testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and sex hormone binding globulin (SHBG) might mediate hormonal risk of ischemic stroke. Additionally, we will examine the adipocyte-derived adiponectin, and retinal binding protein 4 as risk predictors for ischemic stroke in women. Additionally, markers of endothelial inflammation including Lp-PLA2, and IL-18 will be examined. Finally, telomere length, a marker of biologic aging, will be examined. The Nurses' Health Study (NHS) is a prospective cohort study of 121,700 US women, aged 30-55 in 1976. Detailed nutritional, behavioral and lifestyle variables have been collected for more than 25 years, archived blood specimens are available for 31,926 participants (collected1989-1990) and second samples available on 18,700 of these (collected 2000-2001). Based on cases projected through 2008 cycle follow-up, we will analyze 750 nested ischemic stroke case- control pairs for biochemical markers and telomere length. A second sample collected before the stroke will be analyzed on 250 of these pairs. No biochemical or genetic studies for stroke have yet been performed for stroke in this cohort. The proposed grant will establish a separate focus on stroke in the NHS, allowing us to take advantage of the detailed data and large number of events that have accrued. These promising biochemical and genetic markers may have implications for improving prevention strategies, enhancing treatment options and generating additional testable hypotheses for stroke research. PUBLIC HEALTH RELEVANCE: Risk Factors for Ischemic Stroke in Women Stroke is a leading cause of disability and death, yet relatively few biochemical and genetic risk factors for ischemic stroke have been identified. The risk of ischemic stroke has been closely associated with obesity, insulin resistance, and diabetes and this grant will look at related novel risk factors. The proposed grant will establish a separate focus on stroke in the Nurses' Health Study, taking advantage of the detailed data and large number of events that have accrued. These promising biochemical and genetic markers may have implications for improving prevention strategies, enhancing treatment options and generating additional testable hypotheses for stroke research.